ORGN 793 |
P1-site diversity in peptide isostere libraries via smooth CC-couplings on linker reagents
| Jörg Rademann, Medicinal Chemistry / Organic Chemistry, Medicinal Chemistry / Organic Chemistry, FMP and Free University of Berlin, Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, Germany |
| Whereas the combinatorial decoration of preformed isosteric building blocks is the state-of-the-art in protease inhibitor design, diversity in the central P1-position has been difficult to realize so far. We have developed reagent linkers as a novel concept allowing for solid phase CC-couplings under very mild conditions. The strategy was employed to construct several types of peptide isosters (including norstatines, diaminopropanols, and statines) on solid support. All available amino acids could be introduced in the P1-position of peptide isosteres with ease. Thus, without building block synthesis peptide isoster libraries were generated with full variation of all isosteric positions. Moreover, the C-acylations proceeded racemization-free and were followed by stereo-controlled reductions. With the new concept, the effect of P1-site diversity was scrutinized. A library of P1-variants was synthesized and screened against several aspartate proteases. 
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Combinatorial, Parallel, and Solid-Phase Chemistry
1:00 PM-5:00 PM, Thursday, August 26, 2004 Pennsylvania Convention Center -- 202B, Oral
Division of Organic Chemistry
The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004
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